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Simple phenol conjugates of dihydroartemisinin, synthetic method and application

A technology of dihydroartemisinin and synthesis method, applied in the field of chemical medicine, achieving good application prospects, simple synthesis method, and good Wnt signaling channel activation effect

Active Publication Date: 2019-11-22
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the introduction of simple aryl ether fragments and suitable linking structures into DHA molecules has not been reported in the literature at present.

Method used

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  • Simple phenol conjugates of dihydroartemisinin, synthetic method and application
  • Simple phenol conjugates of dihydroartemisinin, synthetic method and application
  • Simple phenol conjugates of dihydroartemisinin, synthetic method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1, Preparation of simple phenolic conjugates of dihydroartemisinin

[0027] (1) The preparation method of intermediate IM1 is as follows:

[0028]

[0029] Add dihydroartemisinin (DHA), diethyl ether and bromohydrin, and add boron trifluoride-diethyl ether (BF 3 ·Et 2 O), under stirring reaction 5 ~ 20h, after the completion of the reaction, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with ethyl acetate (EtOAc, or EA), the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Dry, filter with suction, and remove the solvent from the filtrate under reduced pressure to obtain a crude product, which is recrystallized with petroleum ether (PE)-EA mixed solvent to obtain intermediate IM1.

[0030] (2) DHA simple phenolic conjugates, we use TM3 to represent in this application, its preparation method is as follows:

[0031] In the 100mL reaction bottle, add the raw mater...

Embodiment 2

[0033] Example 2, the preparation results of dihydroartemisinin simple phenolic conjugates

[0034] When n=2 or 3 according to the preparation method described in Example 1, Ar is

[0035]

[0036] When one of them was used, a series of products TM3-1 to TM3-21 were prepared, and the respective reaction conditions, yields, product yields, and product melting points are shown in Table 1.

[0037] Table 1 Experimental results of synthesis of TM3 series compounds

[0038]

[0039]

[0040] Example 3, Characterization data of simple phenolic conjugates of dihydroartemisinin

[0041] A series of products of TM3-1~TM3-21 obtained in embodiment 2 were carried out 1 H NMR (AV-300), 13 C NMR (AV-300) and HR MS (Varian 7.0T) test and characterization, the molecular structure and test data are as follows:

[0042]

[0043] TM3-1(3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyl-10-(3-phenoxypropoxy)decahydro-12H-3,12-epoxy[1,2]dioxepino[ 4,3-i]isochromene

[0044] 1 H NMR (...

Embodiment 4

[0090] Embodiment 4, TM3 target molecule anti-tuberculosis activity test

[0091] U.S. Eli Lilly and Company (Eli Lilly and Company) company tested the anti-tuberculosis activity of the TM3-1~TM3-21 sample that embodiment 2 prepared, at first test the percentage inhibitory rate of single-concentration sample to Mycobacterium tuberculosis; Secondly, highly active molecules are screened out for multi-concentration testing; finally, a variety of cells are tested. The test results are shown in Table 2.

[0092] Table 2 TM3 series target molecules against Mycobacterium tuberculosis H 37 Inhibition rate of Rv

[0093]

[0094]

[0095] It can be seen from Table 2 that at the test concentration of 20 μM, 2 of the 21 compounds had an anti-tuberculosis activity of more than 40%, showing a moderate inhibitory effect on Mycobacterium tuberculosis; at the same time, it was found that the activity of 3-carbon Linker was higher than that of The activity of the linker is weak. Aryl...

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Abstract

The invention discloses simple phenol conjugates of dihydroartemisinin, and belongs to the technical field of chemical medicines. The derivatives or racemates, stereoisomers, tautomers and pharmaceutically acceptable salts thereof have the following general formula shown in the specification, wherein n is 2 or 3. The invention also discloses a synthesis method of the conjugates and application ofthe conjugates in antituberculotic, antidiabetic, lipid-lowering and Wnt signaling pathway agonist active drugs.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to a simple phenolic conjugate of dihydroartemisinin, its synthesis method and application. Background technique [0002] Artemisinin is a sesquiterpene lactone compound containing an endoperoxide group extracted from the plant Artemisia annua, and it is a lead compound of a new type of drug with high efficiency and low toxicity. Dihydroartemisinin (DHA) is the first-generation derivative of artemisinin and the main active metabolite of artemisinin in the body. It not only has a unique structure, but also shows better pharmaceutical properties than artemisinin. , is an important clinical antimalarial drug. In view of the advantages of DHA, such as good absorption, wide distribution, rapid excretion and metabolism, high efficiency, low toxicity, etc., as well as the special structure of DHA, the research on DHA continues. At present, it mainly focuses on the design a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20A61P31/06A61P3/10A61P3/06
CPCC07D493/20A61P31/06A61P3/10A61P3/06Y02A50/30
Inventor 杨大成周福委潘建芳范莉刘建唐雪梅
Owner SOUTHWEST UNIV
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